Menarche-a journey into womanhood: age at menarche and health-related outcomes in East Asians.

STUDY QUESTION: Are there associations of age at menarche (AAM) with health-related outcomes in East Asians? SUMMARY ANSWER: AAM is associated with osteoporosis, Type 2 diabetes (T2D), glaucoma, and uterine fibroids, as demonstrated through observational studies, polygenic risk scores, genetic correlations, and Mendelian randomization (MR), with additional findings indicating a causal effect of BMI and T2D on earlier AAM. WHAT IS KNOWN ALREADY: Puberty timing is linked to adult disease risk, but research predominantly focuses on European populations, with limited studies in other groups. STUDY DESIGN, SIZE, DURATION: We performed an AAM genome-wide association study (GWAS) with 57 890 Han Taiwanese females and examined the association between AAM and 154 disease outcomes using the Taiwanese database. Additionally, we examined genetic correlations between AAM and 113 diseases and 67 phenotypes using Japanese GWAS summary statistics. PARTICIPANTS/MATERIALS, SETTING, METHODS: We performed AAM GWAS and gene-based GWAS studies to obtain summary statistics and identify potential AAM-related genes. We applied phenotype, polygenic risk scores, and genetic correlation analyses of AAM to explore health-related outcomes, using multivariate regression and linkage disequilibrium score regression analyses. We also explored potential bidirectional causal relationships between AAM and related outcomes through univariable and multivariable MR analyses. MAIN RESULTS AND THE ROLE OF CHANCE: Fifteen lead single-nucleotide polymorphisms and 24 distinct genes were associated with AAM in Taiwan. AAM was genetically associated with later menarche and menopause, greater height, increased osteoporosis risk, but lower BMI, and reduced risks of T2D, glaucoma, and uterine fibroids in East Asians. Bidirectional MR analyses indicated that higher BMI/T2D causally leads to earlier AAM. LIMITATIONS, REASONS FOR CAUTION: Our findings were specific to Han Taiwanese individuals, with genetic correlation analyses conducted in East Asians. Further research in other ethnic groups is necessary. WIDER IMPLICATIONS OF THE FINDINGS: Our study provides insights into the genetic architecture of AAM and its health-related outcomes in East Asians, highlighting causal links between BMI/T2D and earlier AAM, which may suggest potential prevention strategies for early puberty. STUDY FUNDING/COMPETING INTEREST(S): The work was supported by China Medical University, Taiwan (CMU110-S-17, CMU110-S-24, CMU110-MF-49, CMU111-SR-158, CMU111-MF-105, CMU111-MF-21, CMU111-S-35, CMU112-SR-30, and CMU112-MF-101), the China Medical University Hospital, Taiwan (DMR-111-062, DMR-111-153, DMR-112-042, DMR-113-038, and DMR-113-103), and the Ministry of Science and Technology, Taiwan (MOST 111-2314-B-039-063-MY3, MOST 111-2314-B-039-064-MY3, MOST 111-2410-H-039-002-MY3, and NSTC 112-2813-C-039-036-B). The funders had no influence on the data collection, analyses, or conclusions of the study. No conflict of interests to declare. TRIAL REGISTRATION NUMBER: N/A.

Polysomnography Is an Important Method for Diagnosing Pediatric Sleep Problems: Experience of One Children's Hospital.

In this study, we collected and analyzed polysomnography (PSG) data to investigate the value of PSG in diagnosing sleep problems in children. The results of PSG studies of children (<18 years old) with sleep problems conducted from April 2015 to May 2017 at a children's hospital in Taiwan were collected and analyzed retrospectively. Data for 310 patients (209 males and 101 females) who underwent PSG were collected. The final diagnoses were as follows: obstructive sleep apnea in 159 (51.3%), snoring in 81 (26.4%), limb movement sleep disorder in 25 (8.1%), hypersomnias in 12 (3.9%), central apnea in 8 (2.9%), enuresis in 7 (2.3%), bruxism in 5 (1.6%), sleep terrors in 5 (1.6%), narcolepsy in 3 (1.0%), sleep seizures in 3 (1.0%), sleep walking in 1 (0.3%), and insomnia in 1 (0.3%). PSG may help detect significant sleep-related problems in children and is useful for making therapeutic decisions regarding children. Obstructive sleep apnea syndrome (OSAS) was the primary sleep problem for most of the children (51.3%); however, only 7.4% of them underwent surgery for OSAS. We therefore suggest that children with sleep problems should undergo PSG.

Greater Protective Potent of s-Methyl Cysteine and Syringic Acid Combination for NGF-differentiated PC12 Cells against Kainic acid-induced Injury.

Objective: The effects of pre-treatments from s-methyl cysteine (SMC) alone, syringic acid (SA) alone and SMC plus SA against kainic acid (KA) induced injury in nerve growth factor (NGF) differentiated PC12 cells were investigated. Methods: NGF-differentiated PC12 cells were treated with 1 µM SMC, 1 µM SA or 0.5 µM SMC plus 0.5 µM SA for 2 days. Subsequently, cells were further treated by 150 µM KA. Results: KA suppressed Bcl-2 mRNA expression, enhanced Bax mRNA expression and casued cell death. SMC was greater than SA, and similar as SMC+SA in increasing Bcl-2 mRNA expression. SMC+SA led to greater increase in mitochondrial membrane potential and cell survival than SMC or SA alone. SMC+SA resulted in more reduction in reactive oxygen species and tumor necrosis factor-alpha generation, more increase in glutathione content and glutathione reductase activity than SMC or SA alone. KA up-regulated protein expression of nuclear factor kappa B (NF-κB) p65 and phosphorylated p38 (p-p38). SMC or SA pre-treatments alone limited protein expression of both factors. SMC+SA resulted in more suppression in NF-κB p65 and p-p38 expression. KA decreased glutamine level, increased glutamate level and stimulated calcium release. SMC pre-treatments alone reversed these alterations. SMC alone elevated glutamine synthetase (GS) activity and mRNA expression. SMC+SA led to greater GS activity and mRNA expression than SMC pre-treatments alone. Conclusion: These findings suggested that this combination, SMC+SA, might provide greater protective potent for neuronal cells.

Whole exome sequencing in Dandy-Walker variant with intellectual disability reveals an activating CIP2A mutation as novel genetic cause.

Dandy-Walker malformation (DWM) has been reported to have heterogeneous causes, including mutations in genes of fibroblast growth factors and in genes in the sonic hedgehog (Shh) signaling pathway. Here, we identified an activating cancerous inhibitor of protein phosphatase 2A (CIP2A) p.D269V mutation, located at the predicted protein-protein interaction groove, as a novel genetic cause of Dandy-Walker variant (DWV). CIP2A has been reported as an oncoprotein promoting tumor survival via inhibition of protein phosphatase 2A (PP2A). However, the impact of human germline CIP2A mutation is unknown. We report a novel heterozygous CIP2A p.D269V mutation via whole exome sequencing in two siblings with DWV and severe intellectual disability who were born to non-consanguineous parents. Only the older brother developed a slow-growing sacral leiomyoma in his teens. The CIP2A p.D269V mutation is associated with increased PP2A, mTOR, and c-Myc protein levels in peripheral blood mononuclear cells (PBMCs). The PP2A phosphatase activity, however, was not suppressed. Deep sequencing revealed that the father carries 16% of somatic CIP2A p.D269V mutation, suggesting potential inheritance from the mosaic sperm populations. Our study is the first to describe a pathogenic CIP2A mutation in humans, which might disrupt neuronal development via enhancing mTOR and c-Myc protein expressions, shedding light in mechanisms of DWV pathogenesis.

Trend of seizure remission in patients with tuberous sclerosis complex: A retrospective medical review.

BACKGROUND: Seizures in tuberous sclerosis complex (TSC) tend to be intractable over time and become a subsequent psychological burden for the patients. The purpose of the current study was to describe the onset, phenotype, and factors associated with seizure remission in patients with TSC. METHODS: Patients diagnosed with TSC between 2009 and 2015 completed a questionnaire interview and underwent a systematic evaluation, including a medical review of their epilepsy history and neurobehavioral disorder assessment. RESULTS: Of the 61 patients, 50 patients (82.0%) had a positive seizure history. The active (n = 34) and seizure remission (n = 16) groups showed significant differences in age, neurobehavioral disorder, history of refractory epilepsy, and onset age (p < 0.001, p < 0.05, p < 0.05, and p < 0.05, respectively). The remission rates were 33.3% and 38.5% for those aged 6-18 years and over 18 years, respectively (p for trend = 0.01). CONCLUSION: Seizure remission can occur in adulthood. It shows a high correlation with patient age, minor refractory epilepsy, and neurobehavioral disorders.

Regression of Neonatal Cardiac Rhabdomyoma in Two Months Through Low-Dose Everolimus Therapy: A Report of Three Cases.

Cardiac rhabdomyoma (CR) is the most common cardiac tumor in newborns. Approximately 75% of cases are associated with tuberous sclerosis complex. Although these tumors usually spontaneously regress after 2 years of age, they can be life-threatening when they obstruct major cardiac inflow or outflow pathways. Everolimus is an inhibitor of the mammalian target of rapamycin, reducing its production of the proteins harmartin and tuberin. Everolimus has demonstrated a remarkable suppression effect in children with tuberous sclerosis complex at doses of 4.7-5.6 mg/M2/day and serum trough levels of 5-15 ng/mL. Since 2012, five case reports of neonates with CR have also reported the tumor-regressing effect of everolimus. However, the optimal dosage for neonates is still unknown. Over the past 2 years, we have deliberately used a low dose everolimus regimen (0.3-0.67 mg/M2/day) in three neonates with large CRs, in an effort to maintain serum trough levels at 3-7 ng/mL. In all three cases, the tumors regressed smoothly within 2 months. Regarding the drug's side effect of predisposing patients to infection, we observed that adenovirus pneumonia occurred in one case at 3 months of age, and chicken pox occurred in another case at 9 months of age; both recovered smoothly. Our three cases of neonatal CR demonstrate that a low-dose everolimus regimen is an effective treatment for tumor regression.

Interleukin (IL)-1beta, IL-1 receptor antagonist, IL-6, IL-8, IL-10, and tumor necrosis factor alpha gene polymorphisms in patients with febrile seizures.

Inflammation and genetics may play a role in the pathogenesis of febrile seizures (FSs). We aimed to test whether interleukin-1beta (IL-1beta), IL-1 receptor antagonist (IL-1 Ra), IL-6 promoter, IL-8, IL-10, or tumor necrosis factor (TNF) gene polymorphisms could be used as markers of susceptibility to FSs. An association study was performed among a cohort of 104 patients with FSs and 143 normal control subjects. There was no significant difference between patients and controls in the distribution of allele frequencies of the IL-1beta promoter, IL-1beta exon 5, IL-6 promoter, IL-8, IL-10, or TNF-alpha gene polymorphisms. In contrast, the IL-1 Ra-I homozygote was more frequent in patients with FSs than in healthy controls (93.2% vs. 83.92%, chi(2)=4.51, P=0.034). In addition, individuals homozygous for the IL-1 Ra-I genotype were more than twice as likely to develop FSs than individuals heterozygous for the IL-1 Ra-I/II genotype (OR, 2.63, 95% CI: 1.08-6.39; chi(2)=4.55, P=0.033). We conclude that the IL-1 Ra gene might be one of the useful markers for predicting susceptibility to FSs.

No association between TAP1 DpnII polymorphism and bronchopulmonary dysplasia.

The possibility that a family history of asthma may have a role in susceptibility to bronchopulmonary dysplasia (BPD) had been raised in several reports, and there was evidence of a strong association between transporter associated with antigen processing (TAP1) polymorphism and asthma in Taiwanese population. To test whether TAP polymorphism has a role in the BPD, we investigated the association between TAP1 polymorphism and BPD by analyzing the results of genotype distribution. The study included 224 ventilated preterm infants (<30 weeks) who had respiratory distress syndrome (RDS) and needed intermittent mandatory ventilation (IMV) during Jan. 1999 to July 2003. The typing of TAP1 polymorphism was performed by polymerase chain reaction (PCR)-based restriction analysis. The demography between two groups of these ventilated preterm infants was not different. We observed no significant differences in genotype distribution or allele frequency of the TAPI polymorphisms between BPD and their respective control infants. There was also no significant difference in genotype distribution of the TAP1 polymorphism with duration of IMV. Therefor, we conclude that TAP1 polymorphism is not a useful marker for predicting the susceptibility or severity to BPD for Taiwanese.

Bacterial meningitis of an infant with Currarino triad.

Currarino triad is a rarely hereditary condition including: (1) an anorectal malformation, (2) an anterior sacral defect, and (3) a presacral mass. Autosomal dominant transmission is suggested. We reported one case of Currarino triad, who was a 3-month-old male with sacral dysgenesis, imperforated anus and enteric cyst. This case presented with acute lower limbs paralysis due to bacterial meningitis complicated with acute arachnoiditis. The diagnosis of this condition led to a work-up of his sibling, who was found to have an incomplete type. The purpose of this case is to emphasize that a high index of suspicion for timely diagnosis and treatment of Currarino triad could prevent devastating complications.